Project Summary The microbes that inhabit the human body are viewed as an integral component of our biology, and microbiome variability has been found to result in differences in disease predisposition. The proposed research will develop and apply methods to infer how variation in the human genome mediates composition and function of the gut microbiome. To achieve this objective, we will pursue four specific aims in an analysis of genome-wide SNP genotype data already available from the TwinsUK project to identify genetic determinants of microbiome composition. For Specific Aim 1, we will use whole- genome sequence data of the twins along with deep metagenomic sequencing of their gut microbiomes to infer heritability and gene-specific associations with a) greater resolution taxonomic data, and b) metabolic attributes of the bacterial community. These data are already in hand, and provide unique opportunities to dissect the means by which variation in the human genome mediates gut microbiome properties. For Specific Aim 2, we will infer individual strains in the gut microbiomes from the metagenomics data, making use of the fact that our sequencing depth is sufficient to identify clonal haplotypes of the most common ~50 bacterial species. The biological impacts of specific strains can vary widely, and this strain-specific analysis is likely to be highly informative by improving specificity and accuracy of associations between host genes and microbiome composition. For Specific Aim 3, we will resample 1000 individuals from the original TwinsUK microbiome survey, and use this information to identify attributes of the gut microbiome that are stable over time, and to test the relationship between heritability and stability of microbes in the microbiome. For Specific Aim 4, we will use the gnotobiotic mouse experimental system to dissect the effects of the heritable bacterium Christensenella minuta on gut function as well has whole-organism physiology. The results of this research will be used to establish links between regions of the human genome and composition of the microbiome. The results of this study have the potential to reveal fundamental human host-microbe interactions that may be applicable to the prevention and treatment of chronic inflammatory diseases.